The electrocardiographic abnormalities in highly trained athletes compared to the genetic study related to causes of unexpected sudden cardiac death

Background: Electrocardiograms in elite endurance athletes sometimes show bizarre patterns suggestive of inherited channelopathies (Brugada syndrome, long QTc, catecholaminergic polymorphic ventricular tachycardia) and cardiomyopathies (arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy) responsible for unexpected sudden cardiac death. Among other methods, genetic analyses are required for correct diagnosis. Objective: To correlate 12– lead electrocardiographic patterns suggestive of inherited channelopathies and cardiomyopathies to specific genetic analyses. Design: Prospective study (2004–2007) of screening 12–lead ECG tracings in standard position and higher intercostal spaces V1 to V3 precordial leads, performed in athletes and normal sedentary subjects aged match. Genetic analyses of subjects with ECG abnormalities suggested inherited channelopathies and cardiomyopathies. Setting: All cardiologic exams and electrocardiograms were performed at ‘Prof. Dr. C.C. Iliescu’ National Institute of Cardiovascular Diseases (Bucharest, Romania). The genetic studies were done at ‘Mina Minovici’ National Institute of Forensic Medicine (Bucharest, Romania). Participants: 347 elite endurance athletes (seniors–190, juniors–157), mean age of 20; 200 subjects mean age of 21, belonging to the control group of 505 normal sedentary population. Results: Seniors. RSR' (V1 to V3) pattern, in 45 cases (23.68%), 5 of them with questionable Brugada sign (elevated J wave and ‘coved’ ST segment,< 2mm in one lead, V1. Typically, Brugada 1 sign was found in one case (0.52%) with no SCN5A abnormalities. One athlete (0.52%) had normal ECG and exon1 SCN5A duplication. MRI confirmed three arrhythmic right ventricular cardiomypathy epsilon waves (1.57%), in one case. ST–segment elevation myocardial injury like in V1–V3 precordial leads in 34 athletes (17.89%).Genetic analyses–no gene mutations. Juniors Upright J wave was found in 43 cases (27.38%). Convex ST segment elevation in V1–V3/V4, in 39 cases (24.84%). Bifid T wave with two distinct peaks was found in 39 cases (24.84%), 5 of them with mild prolonged QTc (0.48 ‘–0.56’) and KCN genes mutations. Nine (5.73%) of the elevated ST segment juniors had questionable Brugada sign, two of which with KCN (n=1) and SCN5A (n=1) gene mutations. Ajmaline provocative test was negative in 4 and was refused by 5 subjects. Conclusion: Bizarre QRS, ST–T patterns suggestive of abnormal impulse conduction in the right ventricle, including the right outflow tract, associated with prolonged QTc interval in some cases were observed in highly trained endurance athletes. The genetic analyses, negative in most athletes, identified surprising mutations in SCN5A and KCN genes in some cases.


© 2009, Carol Davila University Foundation
(Brugada syndrome, long QT syndroms, idiopathic ventricular fibrillation, polymorphic ventricular tachycardia) could be the causes for sudden cardiac death [11][12][13][14]. In the absence of any echocardiographic structural abnormalities, establishing the diagnosis is often difficult to achieve when the electrocardiograms of trained athletes often present findings considered abnormal by usual standards. The correct management includes detailed athlete's history, 12-lead electrocardiography, additional tests (i.e. 24h heart rhythm ambulatory monitoring, Ajmaline provocative test) and sometimes, targeted genetic analysis [15][16][17][18]. A genotype -phenotype analysis based on the electrocardiographic findings in elite endurance athletes was the purpose of our study.

Studied population
Endurance athletes 347 intensively trained athletes (Caucasians) participants in sports activity with high cardiovascular burden were chosen [19,20]. The sports were canoeing, rowing, football, hockey, tennis, swimming, and athletics. There were 190 senior and 157 junior athletes [20]. Senior athletes had trained intensively for 20-27 h /week for > 5 years and participated in World Championships and Olympic Games. The junior primary and final selections were at the age of 12-14 years old and 17-18 years old respectively.

Sedentary healthy population (controls)
The apparently normal (asymptomatic, normal physical examination, no detectable cardiovascular risk factors) sedentary population [21,25] of 505 subjects and participants were investigated for work eligibility in our Cardiology Department (Auto/Work License). Exclusion criteria for control subjects were coronary artery disease, valvular / congenital diseases, cardiomyopathies, heart failure, and cardiovascular drug therapy. None of the athletes and controls received any drugs. The protocol was approved by the Hospital Ethical Committee and informed consents were obtained from all subjects who enrolled in the study.

Clinical examination
The cardiologic examination included detailed personal and family history and complete physical examination [9,11].
Measurements were done according to ASE criteria. (58)

Genetic study
Subjects with positive or questionable ECG patterns of inherited channelopaties / cardiomyopaties were enrolled.

Clinical characteristics of studied population
We examined 347 athletes (seniors 190; juniors 157). Fig. 1 shows the athletes' distribution according to the type of sport and level of training. Brugada sign1, V1-V3 standard / high, one (0.52%) subject; EP induced ventricular tachycardia.
There was a normal echocardiographic exam except for one epsilon subject and for ARVC echo data, diagnosed by MRI. No., number, BSA, body surface area, BP, blood pressure,systolic/diastolic; HR, heart rate.
None of the senior athletes selected for genetic analysis had gene mutations except for one with SCN5 duplication, exon 1 (Fig. 6); normal clinical exam and negative specific tests for Brugada syndrome were done in this case. No SCN5A mutations in Brugada sign1 athlete and EP induced ventricular tachycardia.    One senior athlete had missense mutation (duplication) on SCN5A gene, exon1 (Fig. 6).

Discussions
Since 2004 we have been interested to evaluate the ECG patterns in highly trained athletes from different level of training (juniors, seniors) involved in sports with intensive cardiovascular burden. We observed ECG tracings with bizarre and unexpected QRS and ST-T aspects, different from the "classically" ECG patterns described in elite endurance athletes [20,58-61].
The main purpose of our study was to find out whether these ECG (V1-V3) morphologies (possible delayed impulse conduction in the right ventricle, including RVOT) were linked to genetic mutations responsible for inherited channelopathies (i.e. Brugada syndrome, RVOT ventricular tachycardias) and cardiomyopathies (i.e.ARVC). Gene mutations for HCM in subjects with specific ECG abnormalities were searched for.
The senior and junior athletes' electrocardiograms were analyzed separately and compared to sedentary normal, aged matched persons' ECG data. In seniors, the RSR' pattern dominate with R'>2mm in higher V1-V3 leads; 34% of RSR' athletes had ST-segment elevation, resembling the Brugada sign present in only one lead and V1 (questionable Brugada sign) in few cases. Possible abnormal (delayed) impulse conduction into RVOT has been considered regarding this mechanism [49]. The highest incidence of junior ECG abnormalities was elevated J wave and convex injury like ST-segment elevation in V1-V3,V4 leads (standard, high). In junior athletes, bifid T wave associated to moderately long QTc interval arose the question of a possible abnormal prolonged ventricular repolarization. Few of our controls had similar ECG abnormalities.
A molecular substratum not evident in ordinary life but exacerbated by strenuous training could be the cause of athletes' ECG abnormalities.
To support this hypothesis we focused on the relation between the ECG patterns suggestive of Brugada syndrome, long QT syndrome, HCM, ARVC and specific genetic study.
The genetic analysis referred to mutations in SCN5A and LQTS genes and genes responsible for inherited cardiomyopathies.
Three controls had SCN5A mutations: two of these (deletions) were in 1 Brugada person and his healthy mother. Interestingly, a family member (healthy sister) of a documented ARVC patient had a SNC5A mutation (duplication). All SCN5A mutations were missense, heterozygote type.
No specific molecular abnormalities were found in other athletes.
The mutations identified by MLPA will be detailed by complex genetic analyses such as the sequence techniques.

Conclusions
The electrocardiogram in athletes performing high endurance training is sometimes strange, looking like inherited channelopathy and cardiomyopathy ECG patterns. Specific tests for correct diagnosis are frequently necessary. Genetic analysis, the "last step" to diagnosis sometimes gives surprising and unexpected information, whose significance needs to be investigated. Complex molecular techniques could bring forward details of these genetic mutations identified in elite athletes with "frequently encountered 12-lead ECG athletics patterns".
The next and future medical approach regarding the athletic performance is still a challenge for the scientific medical community.